My career development goal during this Mentored Patient-Oriented Research Career Development Award (K23) is to obtain the skills and training needed to become an independent physician-scientist in patient-oriented research in the immunology of schizophrenia. The Career Development Plan will focus on: 1) increasing my knowledge of monocyte and T-helper lymphocyte subsets, 2) developing an understanding of and experience with modern techniques in immunological research, 3) increasing my knowledge and skills in the design, conduct, and analysis of longitudinal studies, 4) developing a greater understanding and experience with relapse in schizophrenia research, and 5) honing my skills in critical thinking, scientific writing, and presentation. I will apply this knowledge to patient-orinted research to advance our understanding of the pathophysiology and potentially the treatment of relapse in schizophrenia. My research goal is to evaluate serum interleukin-6 (IL-6) levels as a potential clinical state and relapse predictive marker in schizophrenia using novel, complementary cross-sectional and longitudinal approaches. Project # 1 is a longitudinal study of serum IL-6 levels in participants in the NIMH-funded PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) study, a 30-month relapse prevention trial for which blood samples were drawn regularly, and relapse was the primary outcome measure. The primary goal is to determine if changes in serum IL-6 levels predict relapse. Project #2 is a cross-sectional study of serum IL-6 levels, tryptophan catabolites, and leukocyte subsets in relapsed and stable outpatients with schizophrenia, and controls. The primary goal is to evaluate serum IL-6 levels as a potential state marker for acute psychosis. A pathophysiological role for immune abnormalities in schizophrenia, including inflammation, was first hypothesized in 1967, and has been one of the more enduring findings in the field. Recently, increased understanding of the complex interactions between inflammation and the brain in other chronic diseases has better informed this relationship in schizophrenia. Moreover, several randomized, double-blinded trials found that adjunctive treatment with non-steroidal anti-inflammatory drugs (NSAIDs) significantly improved psychopathology in relapsed patients, and serum cytokine levels predicted response to NSAIDs. The confluence of these findings provides important empirical support for a pathophysiological role of inflammation in relapse in some patients with schizophrenia. This application promotes the NIMH Strategic Plan by exploring a novel potential marker for relapse in schizophrenia that could be used to assess treatment effectiveness, inform and advance relapse prevention efforts, and even help pave the way for future immune-based therapeutic interventions. PUBLIC HEALTH RELEVANCE: Schizophrenia is commonly a chronic, debilitating disorder with life-long consequences for affected individuals and families, and the clinical course is often characterized by recurrent relapses, which are associated with adverse outcomes, including increased treatment-resistant symptoms, cognitive decline, and functional disability. This Mentored Patient-Oriented Research Career Development Award (K23) will enable Dr. Brian Miller to further develop his career trajectory in schizophrenia research by exploring a novel potential clinical state and relapse predictive marker in schizophrenia. A better ability to understand and predict relapse in schizophrenia is a compelling opportunity and a public health priority.